Abstract
Mice with monoallelic inactivation of the CBP gene develop highly penetrant, multilineage defects in hematopoietic differentiation and, with advancing age, an increased incidence of hematologic malignancies. The latter are characterized, at least in some cases, by loss of heterozygosity (LOH) at the CBP locus. No such pathology was observed in wild-type or p300 heterozygous null mice of the same age and genetic background. Thus, a full complement of CBP, but not p300, is required for normal hematopoietic differentiation. These results also provide the first experimental evidence for the hypothesis that CBP has tumor-suppressing activity.
MeSH Terms
Animals
Blotting, Southern
Blotting, Western
Bone Marrow Transplantation
CREB-Binding Protein
Cell Transplantation
E1A-Associated p300 Protein
Genes, Tumor Suppressor/genetics
Hematologic Neoplasms/genetics,pathology
Hematopoiesis/genetics
Heterozygote
Loss of Heterozygosity
Mice
Mice, Inbred C57BL
Mice, Knockout
Nuclear Proteins/genetics,metabolism
Phenotype
Spleen/cytology
Trans-Activators/genetics,metabolism
Chemicals
Nuclear Proteins
Trans-Activators
CREB-Binding Protein
Crebbp protein, mouse
E1A-Associated p300 Protein
Ep300 protein, mouse
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Kung A L
Dana-Farber Cancer Institute, and Harvard Medical School, Boston, Massachusetts 02115, USA.
Rebel V I
Bronson R T
Ch'ng L E
Sieff C A
Livingston D M
Yao T P
References (32)
32 references, click to expand
-
The transcriptional coactivators p300 and CBP are histone acetyltransferases.
Cell. 1996 Nov 29;87(5):953-9
PMID: 8945521
-
Identification of c-MYC as a target of the APC pathway.
Science. 1998 Sep 4;281(5382):1509-12
PMID: 9727977
-
The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein.
Nat Genet. 1996 Sep;14(1):33-41
PMID: 8782817
-
p300 and CBP as transcriptional regulators and targets of oncogenic events.
Biol Chem. 1996 Nov;377(11):685-8
PMID: 8960368
-
RNA helicase A mediates association of CBP with RNA polymerase II.
Cell. 1997 Sep 19;90(6):1107-12
PMID: 9323138
-
The morphology, immunohistochemistry, and incidence of hematopoietic neoplasms in mice and rats.
Toxicol Pathol. 1993;21(2):206-18
PMID: 8210943
-
p300 gene alterations in colorectal and gastric carcinomas.
Oncogene. 1996 Apr 4;12(7):1565-9
PMID: 8622873
-
The nuclear hormone receptor coactivator SRC-1 is a specific target of p300.
Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10626-31
PMID: 8855229
-
Experimental plasmacytomagenesis in mice.
Hematol Oncol Clin North Am. 1997 Apr;11(2):323-47
PMID: 9137973
-
Genetic analysis of adenovirus E1A: induction of genetic instability and altered cell morphologic and growth characteristics are segregatable functions.
Mutat Res. 1998 Oct 12;421(1):9-25
PMID: 9748479
-
Mice homozygous for a truncated form of CREB-binding protein exhibit defects in hematopoiesis and vasculo-angiogenesis.
Blood. 1999 May 1;93(9):2771-9
PMID: 10216070
-
Conjunction dysfunction: CBP/p300 in human disease.
Trends Genet. 1998 May;14(5):178-83
PMID: 9613201
-
Chromatin remodeling and leukemia: new therapeutic paradigms.
Blood. 1999 Jul 15;94(2):417-28
PMID: 10397708
-
The CBP co-activator is a histone acetyltransferase.
Nature. 1996 Dec 19-26;384(6610):641-3
PMID: 8967953
-
The molecular role of Myc in growth and transformation: recent discoveries lead to new insights.
FASEB J. 1998 Jun;12(9):633-51
PMID: 9619443
-
The adenovirus E1A-associated 300-kD protein exhibits properties of a transcriptional coactivator and belongs to an evolutionarily conserved family.
Cold Spring Harb Symp Quant Biol. 1994;59:85-95
PMID: 7587135
-
Essential role for the p55 tumor necrosis factor receptor in regulating hematopoiesis at a stem cell level.
J Exp Med. 1999 Nov 15;190(10):1493-504
PMID: 10562323
-
Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP.
Nature. 1995 Jul 27;376(6538):348-51
PMID: 7630403
-
Cellular targets for transformation by the adenovirus E1A proteins.
Cell. 1989 Jan 13;56(1):67-75
PMID: 2521301
-
Drosophila CBP represses the transcription factor TCF to antagonize Wingless signalling.
Nature. 1998 Oct 1;395(6701):521-5
PMID: 9774110
-
Truncated CBP protein leads to classical Rubinstein-Taybi syndrome phenotypes in mice: implications for a dominant-negative mechanism.
Hum Mol Genet. 1999 Mar;8(3):387-96
PMID: 9949198
-
A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A.
Nature. 1996 Jul 25;382(6589):319-24
PMID: 8684459
-
Abnormal skeletal patterning in embryos lacking a single Cbp allele: a partial similarity with Rubinstein-Taybi syndrome.
Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10215-20
PMID: 9294190
-
Definition of adenovirus type 5 functions involved in the induction of chromosomal aberrations in human cells.
J Gen Virol. 1990 Apr;71 ( Pt 4):801-8
PMID: 2139107
-
CREB-binding protein cooperates with transcription factor GATA-1 and is required for erythroid differentiation.
Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2061-6
PMID: 9482838
-
The murine gene p27Kip1 is haplo-insufficient for tumour suppression.
Nature. 1998 Nov 12;396(6707):177-80
PMID: 9823898
-
MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3).
Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8732-7
PMID: 9238046
-
Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain.
Cell. 1997 Aug 22;90(4):595-606
PMID: 9288740
-
Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300.
Cell. 1998 May 1;93(3):361-72
PMID: 9590171
-
Tumors in Rubinstein-Taybi syndrome.
Am J Med Genet. 1995 Mar 13;56(1):112-5
PMID: 7747773
-
Independent transformation activity by adenovirus-5 E1A-conserved regions 1 or 2 mutants.
Virology. 1991 Jun;182(2):553-61
PMID: 1827227
-
The p300/CBP family: integrating signals with transcription factors and chromatin.
Trends Cell Biol. 1997 Jun;7(6):230-6
PMID: 17708951